The overarching aim of this grant from its inception in 1990 has been to use animal models to gain a better understanding of neuronal systems that may be dysfunctional in schizophrenia. The neuronal networks that we have focused on have included dopamine innervated regions, and the glutamatergic regulation of these regions. While studies supported by this grant and work by others have provided a number of potential novel targets for treating schizophrenia, the enthusiasm that we will discover treatments that will cure or even provide far more superior efficacy than current antipsychotic medications has been dampened by our increased appreciation of the complexity of genetic and non-genetic causes of schizophrenia. It is increasingly evident that, by the time the illness presents itself, he damage (the miswiring resulting in functional lesions) may be irreversible. Thus, one of our best chances for treating this illness is to prevent its progression. Specifically, the clinical fild has advanced toward identifying individuals at the prodromal phase of the illness who are at high risk for psychosis, the great majority of whom are adolescents or young adults, with the hope that appropriate interventions in these individuals will prevent transition to the psychotic illness. The efforts to design safe and mechanistically driven interventions, however, are hampered seriously by our poor knowledge of the neurobiology of the adolescent brain. The overarching aim of this application is to gain a better functional understanding of neuronal systems that may be relevant to adolescent vulnerability to develop schizophrenia. The experimental design is guided by complementary clinical findings in individuals at-risk (AR) for schizophrenia and our own basic findings in adolescent rats. Human imaging findings in AR individuals report that the onset of psychosis is preceded by abnormal presynaptic dopamine activity in the associational as opposed to ventral regions of striatum, and that this measure correlates with altered prefrontal cortex (PFC) function. Our animal studies identify key differences in presynaptic dopamine activity in the dorsal striatum, and in the processing of salient information in the dorsal striatum and PFC of adolescent compared to adult rats. Collectively, these parallel findings suggest that the disruption of cortical networks that regulat dopamine projections to cortical and dorsal regions of the striatum may be relevant to increased vulnerability to transition to psychosis. Given this, we propose the working hypothesis that midbrain dopamine systems, and their interactions with striatal and PFC areas, are regulated differently in adolescents compared to adults. We address this hypothesis at multiple levels of analysis by using state-of-the-art methods to compare local and global functions of dopamine neurons in adolescents and adult rats. Regardless of the outcome, the data generated by the proposed experiments will inform us about brain circuits that subserve affective and cognitive behaviors in adolescents, and will provide a platform for future investigations toward intervention strategies in AR individuals.